Uptake and metabolic effects of 3-iodothyronamine in rat liver

Objectives: 3-iodothyronamine (T1AM) is an endogenous thyroid hormone derivative able to interact with trace amine associated receptors, a family of G protein-coupled receptors, and possibly with other specific molecular targets. Since T1AM has been suggested to produce metabolic effects, in the present work we investigated whether T1AM is taken up by hepatocytes and whether it is able to affect liver metabolism. Methods: Human hepatocellular carcinoma cells (HepG2) were exposed to exogenous T1AM (1μM) for 5-300 min, then T1AM and its putative catabolites, namely thyronamine (T0AM), 3-iodothyroacetic acid (TA1) and thyroacetic acid (TA0), were assayed in the incubation medium and in cell lysate by HPLC coupled to tandem mass spectrometry. In other experiments T1AM was infused in an isolated rat liver preparation perfused with Krebs-Henseleit buffer. The effluent perfusate was then collected for 60 min at 5 min intervals to measure the release of glucose, lactate, pyruvate and ketone bodies (acetoacetate and beta-hydroxybutyrate). Results: T1AM was taken up by HepG2 cells, and since 5 min lysate concentration exceeded medium concentration by over 5-fold. After 300 min, about 80% of total T1AM was recovered unchanged, while less than 10% was converted into TA1. Minimum amounts of T0AM were observed while TA0 was undetectable. Similar results were observed in perfused rat liver, since tissue T1AM concentration exceeded 100 pmol/g after a 60 min infusion of 50 nM T1AM. In this model, infusion of 1 μM T1AM did not produce any significant change in glucose, lactate and pyruvate release, while acetoacetate and beta-hydroxybutyrate release increased significantly (0.027±0.003 vs 0.015±0.002 μmol/min per g, and 0.075±0.001 vs 0.031±0.001 μmol/min per g, P< 0.01 in both cases). Conclusions: We conclude that exogenous T1AM is taken up by hepatocytes, where it is partly deaminated to TA1 and stimulates ketogenesis.